The spontaneous diabetic syndrome in the "BB" (Bio Breeding Laboratories, Ottawa) Wistar-derived rat was discovered in 1974 and systematically examined by this laboratory since 1975. In collaboration with Dr. Arthur A. Like (University of Massachussets, Worcester) we have demonstrated the syndrome to be caused by a dramatic inflammatory pancreatic islet lesion ("insulitis"), apparently specific to beta cells. The extent of beta cell destruction, and its time course, determine the severity and course of the clinical syndrome. Obesity is absent. We have observed fulminant ketotic diabetes, over diabetes with mild ketosis, "chemical" diabetes (abnormal glucose tolerance tests) and remission following periods of glycosuria. Progression from milder to more severe forms also occurs, sometimes with intervals of hyperinsulinemia preceding hypoinsulinemia. Comprehensive studies of weights, fluid balance, food intake, circulating hormones and substrates, responses to secretagogues, and pancreatic hormone content and light microscopy have been performed. The etiology is not known, though a genetic factor exists, and is the subject of detailed study (A.A. Like, L. Butler). The present request has four phases. 1. To characterize forms and natural histories of diabetes in litters from selected inbred lines now being developed. This will involve monitoring the same variables previously studied in non-inbred rats, (to define the optimum conditions for subsequent detailed studies of etiology). 2. To extend knowledge of the abnormal hormone secretion by in vitro study of biosynthesis and release in a static system (isolated islets), and a dynamic system (isolated, perfused pancreas). 3. To perform a detailed study of the role of the autonomic nervous system in the disorder of glucagon secretion in overt diabetes, in vivo. Secretion during immobilizaton stress will be studied with and without blocking agents, with monitoring of circulating catecholamines. 4. To determine inferentially whether an immunologic component exists in the pathogenesis, immunosuppressive agents will be given to rats with chemical diabetes and newly-discovered glycosuria. From each rat which is sacrificed appropriate samples will be submitted to collaborators for viral, pathologic, metabolic and hormonal studies.